Amino derivatives of nu-cyclopropylbenzylamines



United States Patent The present invention is concerned with compounds corresponding to the formula Y (CHM-R and methods for their preparation. In this and succeed- .ing formulas, X and Y are each independently selected from the group consisting of hydrogen, loweralkyl, chlorine, bromine, hydroxy, lowcralkoxy, amino and loweralkylamino, n is a number from 2 to 4, inclusive, and

R represents amino, monoloweralkylarnino, dilower'alkylamino, piperidyl, pyridyl or morpholino. The terms loweralkyl and loweralkoxy as employed herein refer to the alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, inclusive.

These new compounds are colorless liquids readily soluble in many organic solvents but substantially insoluble in Water. They are useful as monoamine oxidase inhibitors and as such can be administered orally per se or admixed with a non-toxic, pharmaceutical carrier to warm-blooded animals in order to improve or completely eliminate the annoying symptoms of depression. In a representative operation, N-cyclopropyl N-(B-diethylaminoethyl)-benzylamine completely inhibited the depressing eifects of monoamine oxidase in mice when administered orally at a dosage of 25 mg. per kg. of body weight.

The compounds wherein R is diloweralkylamino, piperidyl, pyridyl or morpholino can be readily prepared by reacting equimolar proportions of a cyclopropylamine of the formula with a compound of the formula rnorpholino and Hal is chlorine or bromine. The reaction is preferably carried out at the reflux temperature in the presence of an inert solvent such as ethanol and a hydrohalide acceptor such as sodium carbonate. When the reaction is complete, any solids which form are removed by filtration, the solvent removed from the filtrate and the residue extracted with ether. Upon distillation of the ether extracts under reduced pressure, the desired products are obtained as colorless liquids.

The compounds wherein R is amino or monoloweralkylamino are prepared as shown in the following series of reactions in which Z is OH, Br or Cl and R" is hydrogen or loweralkyl:

1 X CH2 Patented Oct. 13,1964

Reaction 1 is carried out by dissolving the cyclopropylamine in an inert solvent such as methanol and adding an equimolar amount of the nitrile compound thereto at a temperature of about 0 C. The solvent is thereafter removed and the residue fractionally distilled. Reactions 2 and 4 are performed by dissolving lithium aluminum hydride in ether and adding thereto an equimolarproportion of the intermediate product prepared in Reactions 1 and 3 at such a rate as to maintain gentle reflux. Following the addition, the reaction mixture is refluxed for about 4 hours to complete the reaction. The complex formed is then decomposed with water, the. solvent is removed and the residue fractionally distilled. Reaction 3 is carried out by refluxing the appropriate benzylamine with a stoichiometric excess of an ethyl ester or acid chloride, removing said excess ester or acid chloride upon completion of the reaction and distilling the residue under reduced pressure. I

The following examples which are described in detail merely illustrate some specific embodiments of the invention but are not to be construed as limiting.

EXAMPLE 1 N-Cyclopropyl-N-(fl-Diethylaminoethyl)-Benzylamine A mixture of 29.4 grams (0.2 mole) of N-cyclopropylbenzylamine, 34.4 grams (0.2 mole) of ,B-diethylarninoethyl chloride, 31.8 grams (0.3 mole) of anhydrous sodi- G EXAMPLE 2 By reacting equimolccular proportions of N-cyclopropyl- N -p-chlorobenzylamine and B-dimethylaminoethyl chloride as described in Example 1, there is obtained N- cyclopropyl-N-(p-dimethylaminoethyl) p chlorobenzylamine having the formula CH 01 'OH2?I-CHCH CHz z w ah the dihydrochloride salt of which melts at 186 C.

EXAMPLE 3 The reaction of N-cyclopropyl-N 3,4 dichlorobenzylamine with B-diethylaminoethyl bromide in the same manner as that described in Example 1 results in the formation of N-cyclopropyl-N (B diethylaminoethyl)- 3,4-dichlorobenzylamine of the formula which boils at 160 C. at 1 mm. pressure and has a refractive index mi of 1.5240.

EXAMPLE4 By substituting N-cyclopropyl-N-o-bromobenzylamine for the N-cyclopropylbenzylan'iine in Example 1, one obtains N-cyclopropyl-N-(fi-diethylaminoethyl) o bromobenzylamine corresponding to the formula HsCO is readily obtained by reacting N-cyclopropyl-N-3,4-dimethoxybenzylamine with ,8-diethylaminoethyl chloride in the same manneras that described in Example 1. The product has a boiling point of 171-173 C. at 0.5 mm. pressure and a refractive index n of 1.5134.

If desired, ,B-dipropylaminoethyl chloride, ,B-dibutylaminoethyl bromide, 'y-dibutylamin opropyl chloride, A-dibutylaminobutyl bromide, fl-pyridylethyl chloride, 'y-pyridylpropyl chloride, A-pyridylbutyl chloride, 18-piperidylethyl chloride, 'y-piperidylpropyl chloride, A-piperidylbutyl chloride, fl-morpholinoethyl bromide, 'y-rnorpholinopropyl bromide or A-morpholinobutyl chloride can be reacted as described in the foregoing examples with other cyclopropyl benzylarnines such as N-cyclopropyl-N-pbromobenzylamine, N-cyclopropyl-N-2,4-dibromobenzylamine, N-cyclopropyl-N-p-methylbenzylamine, N-cyclopropyl-N-o-butylbenzylamine, N-cyclopropyl-N 2,6 diethylbenzylamine, N-cyclopropyl-N-3,4-dipropylbenzylamine, N-cyclopropyl-N-rn-hydroxybenzylamine, N-cyclopropyl-N-p-butoxybenzylamine, N-cyclopropyl-N 3,5-diethoxybenzylamine, N-cyclopropyl-N 0 aminobenzylamine, N-cyclopropyl-N-p-methylarninobenzylamine, N-cycyclop'ropyl-N-o-propylaminobenzylamine, N-cyclopropyl- N-2,4-diethylaminobenzylamine or N'-cyclopropyl-N-2,6- dibutylarriinobenzylamine to obtain the corresponding amino derivatives of the cyclopropylbenzylamines employed, all of which compounds are considered to be within the scope of the present invention.

4 EXAMPLE 6 N -Cycl opropyl-N ,B-A minaethyl -Ben zylamine A solution of 99 grams (0.65 mole) of N-cyclopropylamine in 150 ml. of methanol was cooled to 0 C. and added dropwise with stirring to 53 grams (0.65 mole) of glycolonitrile. The temperature was maintained below 5 C. during the addition. When the addition was complete, the reaction mixture was stirred at 5 C. for minutes and thereafter allowed to stand at room temperature overnight. The solvent was then removed and the residue fractionally distilled to obtain the intermediate N-cyclopropyl-N-cyanomethyl-benzylamine which boiled at 133-135 C. at 0.9 mm. pressure and had a refractive index 12 of 1.5161.

In the second step of the reaction, 37.2 grams (0.2 mole) of N-cyclopropyl-N-cyanomethyl-benzylamine was dissolved in 100ml. of ether and added slowly to 7.6 grams (0.2 mole) of lithium aluminum hydride in 250 ml. of ether at such a rate that gentle reflux was maintained. The reaction mixture was then refluxed for 3 hours. The complex which formed was decomposed by the succssive' addition of 7.2 ml. of water, 7.2 ml. of 15% aqueous sodium hydroxide solution and 21.6 ml. of water. Afterfiltering and removing the ether, the residue was distilled to obtain the N-cyclopropyl-N-([3-aminoethyl)- benzylamin'e product boiling at 126128 C. at 0.5 mm. pressure and having a refractive index li =1.5254.

EXAMPLE 7 CH CH CH NHz which boils at 136 C. at 5 mm. pressure and has a refractive index 11 of 1.5232.

In a similar manner, any compound of the formula can be reacted with glycolonitrile, 3-bromopropionitrile or 4-chlorobutyronitrile to obtain the corresponding N- cyclopropyLN-cyanoalkyl-benzylamines which when reduced with lithium aluminum hydride result in the forma tion of compounds of the formula Y (0 H2) u-NH EXAMPLE 8 N -Cycl0pr0pyl-N [i-M eflzylaminoethyl -Bcnzy lam ine CH CH NHCH A mixture of 49 grams (0.25 mole) of N-cyclopropyl- N-(B-aminoethyl)-benzy1amine and 29 grams (0.40 mole) of ethyl formate was refluxed for 24 hours. The excess ethyl formate was removed and the residue distilled to obtain the intermediate N-cyc1opropyl-N-( fi-formylaminoethyD-benzylamine which boiled at l64166 C. at 0.6

mm. pressure and had a refractive index n of 1.5361. Thereafter, 32.6 grams (0.14 mole) of the intermediate product in 100 ml. of ether was added to 5.31 grams (0.14 mole) of lithium aluminum hydride in 250 ml. of ether at such a rate as' to maintain gentle reflux. The reaction mixture was then stirred and refluxed for 4 hours. Thecomplex which formed was decomposed by adding successively 5 ml. of water, 5 ml. of aqueous sodium hydroxide solution and 15 ml. of water. After filtering and evaporating the ether, the residue was fractionally distilled to obtain the desired N-cyclopropyl-N-(pi-methylaminoethyl)-benzylamine boiling at 95-96 C. at 1 mm. pressure and having a refractive index n,; of 1.5148.

EXAMPLE 9 Y z)n H2 can be reacted with ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate or a loweralkyl acid chloride to obtain the corresponding substituted N-cyclopropyl-N- benzylamines of the formula wherein R" is hydrogen or lower alkyl which upon reduction with LiAlH result in the formation of compounds of the formula Y 2) r-NH-lower alkyl The cyclopropylbenzylamines employed as starting materials in the present invention can be readily prepared by reaction at room temperature of equimolecular proportions of cyclopropylamine with an aldehyde of the formula followed by distillation of the reaction mixture to obtain an intermediate of the formula which is then reduced with hydrogen at room temperature in the presence of a palladium catalyst. Thus, N-cyclopropylbenzylamine boils at 8l C. at 5 mm. pressure.

CH2 5 CHrN-C CE2 Y JHZ),,R wherein X and Y are each independently selected from the group consisting of hydrogen, loweralkyl, chlorine, bromine, hydroxy, loweralkoxy, amino and lower alkylamino, n is a number from 2 to 4, inclusive, and R is a member of the group consisting of amino, monoloweralkylamino, diloweralkylamino, piperidyl, pyridyl and morpholino.

2. N-cyclopropyl N (B-diethylaminoethyl)-benzylamine.

3. N-cyclopropyl N (,B-dimethylaminoethyl)-benzylamine.

4. N-cyclopropyl N (B-diethylaminoethyl)-3,4-dichlorobenzylamine. 5. N-cyclopropyl N (B-diethylaminoethyl)-o-bromobenzylamine.

6. N-cyclopropyl N (B-diethylaminoethyl)-3,4-dimethoxybenzylamine.

7. N-cyclopropyl-N- (B-aminoethyl) -benzy1amine.

8. N-cyclopropyl-N-('y-aminopropyl)-benzylamine.

9. N-cyclopropyl N (B-methylaminoethyl)-benzylamine.

10. N-cyclopropyl N ('y-methylaminopropyl) -benzylamine.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Wagner et al.: Synthetic Organic Chemistry, p. 659 (1953). 

1. COMPOUNDS OF THE FORMULA 